This invention relates to stabilized dry powder formulations used for treatment of respiratory conditions, such as asthma. The invention further relates to the use of a polar bronchodilator in combination with a less polar anti-inflammatory drug for treating respiratory conditions.
Within the past 30 years, asthma has become increasingly prevalent, especially among children. Despite asthma drug therapy, asthma is still a serious and potentially fatal disease. Asthma is now recognized as a chronic inflammatory disease. A common cause for asthma attacks is poor compliance with long-term treatments, such as inhaled steroids. These do not provide immediate relief. On the other hand, patients will readily take bronchodilators using inhalers, since these provide rapid relief of symptoms.
Fluticasone propionate [(6 alpha, 11 beta, 16 alpha, 17 alpha)-6,9,-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester] is an anti-inflanmmatory drug. It has been used to reduce inflammation in airways. As a nasal spray it is used for rhinitis or inflammation of the nose. It has been used in inhalers for breathing problems like asthma, chronic bronchitis or emphysema.
Fluticasone propionate (referred to herein simply as xe2x80x9cfluticasonexe2x80x9d) is a steroid which reduces the inflammation of nasal passages or bronchial tissue to make breathing easier. Its mechanism of the anti-inflammatory activity in general, is unclear. However, it is thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It has been postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Chemically, fluticasone propionate is C25H31F3O5S. It is non-polar and insoluble in water.
Formoterol fumarate, (N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]formamide), (referred to herein as xe2x80x9cformoterolxe2x80x9d) is a long acting beta agonist which selectively stimulates xcex22-receptors. It is a bronchodilator which relaxes the bronchial smooth muscle, making breathing easier. Inhaled formoterol acts rapidly, usually within minutes. Inhaled formoterol also exerts a prolonged bronchodilation, which in clinical trials has been demonstrated for up to 12 hours. Formoterol is polar and is soluble in water.
Most bronchodilators have relatively short duration of action. By using a compound with long duration e.g. formoterol, with an anti-inflammatory, such as fluticasone, improved therapy can be realized.
With these and other powder formulation drugs, physical stability is often difficult to maintain, when the powder is exposed to humidity in the environment, typically after the powder or dose container is removed from its sealed pouch or package. In the presence of water vapor, active powder drug particles used for inhalation, which are preferably in the 1-10 micron range, tend to fuse together into larger particles. As this occurs, the respirable dose is reduced, because the larger particles deposit out on the mouth, throat, or bronchi, and do not reach the deeper lung. This fusing of particles may occur more rapidly, and with greater detrimental effect, when the formulation has active and excipient particles, ( or two or more types of active drug particles) which are both polar, or which are both non-polar.